Development of Novel Therapeutics for the Treatment of Alzheimer's Disease

开发治疗阿尔茨海默病的新疗法

• 批准号: 10121243
• 负责人: MARK T QUINN
• 金额: $ 33.75万
• 依托单位: MONTANA STATE UNIVERSITY - BOZEMAN
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10121243
• 关键词: Abeta synthesis; Address; Adult; Affect; Agonist; Alaska Native; Alzheimer' s Disease; Alzheimer' s disease related dementia; Alzheimer' s disease risk; American Indians; Amyloid beta-42; Amyloid beta-Protein; Area; Beta Cell; Binding; Biological Markers; Cause of Death; Cell surface; Cells; Cellular biology; Communities; Dementia; Development; Disease; Dose; Epidemic; Evaluation; Event; FPR1 gene; FPR2 gene; Future; Gene Expression; High Prevalence; Human; Immune system; Immunotherapeutic agent; Individual; Inflammation; Inflammatory; Inflammatory Response; Interruption; Knowledge; Lead; Letters; Libraries; Ligands; Lipopolysaccharides; Microglia; Molecular; Monitor; Nerve Degeneration; Nuclear; Pathogenesis; Pathology; Pathway interactions; Phagocytes; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phenotype; Play; Presenile Alzheimer Dementia; Production; Reactive Oxygen Species; Research; Risk Factors; Role; Signal Transduction; Specificity; Structure-Activity Relationship; Switch Genes; Testing; Therapeutic; Therapeutic Agents; Therapeutic Intervention; United States; abeta oligomer; amyloid peptide; analog; animal model development; base; chemokine; cytokine; dementia risk; drug development; drug discovery; fMet-Leu-Phe receptor; formyl peptide; immunopharmacology; inhibitor/antagonist; innovation; insight; molecular modeling; monocyte; neuroinflammation; new therapeutic target; novel; novel strategies; novel therapeutics; preclinical study; prevent; prospective; receptor; response; screening; signal recognition particle receptor; small molecule; success; therapeutic target; transcriptome sequencing; uptake

Alzheimer’s disease (AD) is the most common cause of dementia and is the sixth leading cause of death in the United States. More than 5.8 million people live with AD today, and it is projected that by the year 2050, nearly 14 million people will be affected by this devastating disease. For American Indian and Alaska Native (AI/AN) communities, the effects of AD and related dementias (ADRD) will likely have an even greater impact because of the higher prevalence of risk factors associated with AD/ADRD. Indeed, the number of AI/ANs living with dementia is projected to grow over five-fold by 2060. This increase in the number of older AI/AN adults living with dementia will have a significant and detrimental impact on the vitality of whole communities. In order to address this epidemic, new therapeutics are needed that target specific pathways associated with AD/ADRD pathogenesis. For example, a significant amount of research suggests that neuroinflammation plays an active role in AD pathogenesis and that microglial cells bind to soluble amyloid β (Aβ) oligomers and Aβ fibrils via cell- surface formyl peptide receptor 2 (FPR2), resulting in an inflammatory response. Thus, we hypothesize that specific therapeutics that target and disrupt microglial cell activation pathways and inflammatory polarization could interrupt the harmful inflammatory events contributing to AD pathogenesis and favor a microglial M2 polarization that resolves inflammation. We propose to address this hypothesis by characterizing the human microglial inflammatory responses induced by soluble and aggregated Aβ, including intracellular Ca2+ flux, reactive oxygen species (ROS) production, cytokine/chemokine production, and nuclear factor κB (NF-κB) activation. We will also characterize microglial inflammatory phenotype switching (M1/M2) and gene expression (RNA-Seq) in response to Aβ activation. We will then evaluate effects of novel small molecule FPR2 antagonists on human microglial cell inflammatory responses to determine which compounds are effective inhibitors of inflammation and can enhance microglial M2 polarization. We have discovered a large number of FPR2 ligands over the years, including some specific for FPR2 and some with mixed receptor specificity for FPR1/FPR2, which can be biased towards FPR2. This library of FPR2 ligands will be useful for initial screening but will be followed by structure-activity relationship (SAR) analysis, molecular modeling, and acquisition/synthesis of new analogs. The accomplishment of these preclinical studies will lead to the development of a new class of prospective compounds that could be developed for the treatment of AD/ADRD, which could significantly benefit the AI/AN Communities. This is clearly an innovative approach to treating a prevalent disease where there are few effective drugs. The proposal will also address significant knowledge gaps relevant to the mechanisms of microglial inflammation induced by amyloid peptides. Further testing in an animal model and development of the most promising candidate FPR2 ligands will be pursued in a future proposal.

阿尔茨海默病(AD)是导致痴呆症的最常见原因，是#年全球第六大致死原因 美国。今天有超过580万人患有AD，据预测，到2050年， 近1400万人将受到这种毁灭性疾病的影响。对于美国印第安人和阿拉斯加原住民 (AI/AN)社区，AD和相关痴呆症(ADRD)的影响可能会产生更大的影响 因为与AD/ADRD相关的危险因素的患病率较高。事实上，活着的人工智能/人工智能的数量 据预测，到2060年，痴呆症患者将增长五倍以上。老年人工智能/人工智能成年人数量的增加 患有痴呆症将对整个社区的活力产生重大和有害的影响。按顺序 为了应对这一流行病，需要针对与AD/ADRD相关的特定途径的新疗法 发病机制。例如，大量研究表明，神经炎症在 小胶质细胞与可溶性淀粉样蛋白β(A-β)寡聚体和A-β纤维结合在AD发病中的作用 表面甲酰肽受体2(FPR2)，导致炎症反应。因此，我们假设 靶向和干扰小胶质细胞激活途径和炎症的特定疗法 极化可以阻断导致AD发病的有害炎症事件 一种小胶质细胞M2极化，可消除炎症。 我们建议通过表征人类小胶质细胞炎症反应来解决这一假说。 可溶性和聚集性A-β诱导的细胞内钙离子通量、活性氧自由基(ROS) 产生、细胞因子/趋化因子产生和核因子κB(NF-κB)激活。我们还将描述 小胶质细胞炎性表型转换(M1/M2)和基因表达(RNASeq)对Aβ的反应 激活。然后我们将评估新型小分子FPR2拮抗剂对人小胶质细胞的影响 炎症反应，以确定哪些化合物是有效的炎症抑制剂，并可以增强 小胶质细胞M2极化。多年来，我们已经发现了大量的FPR2配体，包括一些 一些是FPR2特异性的，有些是FPR1/FPR2的混合受体特异性的，这可能偏向FPR2。 这个FPR2配体文库将对初始筛选有用，但随后将进行结构-活性关系 (合成孔径雷达)分析、分子模拟和新类似物的获取/合成。 这些临床前研究的完成将导致开发一类新的 可开发用于治疗AD/ADRD的预期化合物，这可能 显著受益于AI/AN社区。这显然是一种治疗流行的 几乎没有有效药物的疾病。该提案还将解决有关的重大知识差距。 淀粉样多肽诱导小胶质细胞炎症的机制。在动物模型上的进一步试验 最有希望的候选FPR2配体的开发将在未来的提案中进行。

项目成果

Amino Acid Trp: The Far Out Impacts of Host and Commensal Tryptophan Metabolism.

• DOI: 10.3389/fimmu.2021.653208
• 发表时间: 2021
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Grifka-Walk HM;Jenkins BR;Kominsky DJ
• 通讯作者: Kominsky DJ

Chemical Composition and Immunomodulatory Activity of Essential Oils from Rhododendron albiflorum.

• DOI: 10.3390/molecules26123652
• 发表时间: 2021-06-15
• 期刊: Molecules (Basel, Switzerland)
• 作者: Schepetkin IA;Özek G;Özek T;Kirpotina LN;Khlebnikov AI;Quinn MT
• 通讯作者: Quinn MT

Novel c-Jun N-Terminal Kinase (JNK) Inhibitors with an 11H-Indeno[1,2-b]quinoxalin-11-one Scaffold.

• DOI: 10.3390/molecules26185688
• 发表时间: 2021-09-20
• 期刊: Molecules (Basel, Switzerland)
• 作者: Liakhov SA;Schepetkin IA;Karpenko OS;Duma HI;Haidarzhy NM;Kirpotina LN;Kovrizhina AR;Khlebnikov AI;Bagryanskaya IY;Quinn MT
• 通讯作者: Quinn MT

Elder-led cultural identity program as counterspace at a public university: Narratives on sense of community, empowering settings, and empowerment.

老年人主导的文化认同计划作为公立大学的反空间：关于社区意识、赋权环境和赋权的叙述。

• DOI: 10.1002/ajcp.12673
• 发表时间: 2023
• 期刊: American journal of community psychology
• 影响因子: 3.1
• 作者: Buckingham,SaraL;Schroeder,TieraUqiilaq;Hutchinson,JacyR
• 通讯作者: Hutchinson,JacyR

Investigation of the 2018 thick-billed murre (Uria lomvia) die-off on St. Lawrence Island rules out food shortage as the cause.

对 2018 年圣劳伦斯岛厚嘴海鸦 (Uria lomvia) 死亡事件的调查排除了食物短缺的原因。

• DOI: 10.1016/j.dsr2.2020.104879
• 发表时间: 2020
• 期刊: Deep-sea research. Part II, Topical studies in oceanography
• 作者: Will,Alexis;Thiebot,Jean-Baptiste;Ip,HonS;Shoogukwruk,Punguk;Annogiyuk,Morgan;Takahashi,Akinori;Shearn-Bochsler,Valerie;Killian,MaryLea;Torchetti,Mia;Kitaysky,Alexander
• 通讯作者: Kitaysky,Alexander